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Cellular defense against H2O2-induced apoptosis via MAP kinase-MKP-1 pathway

Qihe Xu1, Tsuneo Konta, Kenji Nakayama

  • 1Department of Medicine, Royal Free and University College Medical School, University College London, London, England, United Kingdom.

Free Radical Biology & Medicine
|April 3, 2004
PubMed

Insights

Mitogen-activated protein kinase phosphatase-1 (MKP-1) guards rat mesangial cells against oxidative stress. Hydrogen peroxide (H2O2) upregulates MKP-1 via the MAP kinase-AP-1 pathway, preventing apoptosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) is an oxidative stress-inducible gene.
  • Understanding the regulation and function of MKP-1 in cellular responses to oxidative stress is crucial.

Purpose of the Study:

  • To investigate the signaling pathways regulating oxidative stress-induced MKP-1 expression.
  • To determine the role of MKP-1 in apoptosis of rat mesangial cells exposed to oxidative stress.

Main Methods:

  • Northern and Western blot analyses to assess MKP-1 mRNA and protein levels.
  • Use of selective MAP kinase inhibitors and dominant-negative c-jun mutants.
  • Treatment with vanadate (protein tyrosine phosphatase inhibitor) and transfection with wild-type or mutant MKP-1.

Main Results:

  • Hydrogen peroxide (H2O2) induced MKP-1 expression in a dose-dependent manner.
  • H2O2 activated extracellular signal-regulated kinase, p38 MAP kinase, c-Jun N-terminal kinase, and activator protein 1 (AP-1).
  • MAP kinase and AP-1 pathways mediated H2O2-induced MKP-1 expression, and MKP-1 inhibited H2O2-induced apoptosis.

Conclusions:

  • MKP-1 induction by H2O2 is mediated by the MAP kinase-AP-1 pathway.
  • MKP-1 plays a protective role in cellular defense against oxidative stress-induced apoptosis in mesangial cells.

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